Journal of the American Heart Association
CONTEMPORARY REVIEW
Exploring Refractoriness as an Adjunctive
Electrical Biomarker for Staging of Atrial
Fibrillation
Lianne N. van Staveren, MD; Natasja M. S. de Groot , MD, PhD
ABSTRACT: Patients diagnosed with the same subtype of atrial fibrillation according to our current classification system may differ in symptom severity, severity of the arrhythmogenic substrate, and response to antiarrhythmic therapy. Hence, there is a need for an electrical biomarker as an indicator of the arrhythmogenic substrate underlying atrial fibrillation enabling patient-tailored therapy. The aim of this review is to investigate whether atrial refractoriness, a well-known electrophysiological parameter that is affected by electrical remodeling, can be used as an electrical biomarker of the arrhythmogenic substrate underlying atrial fibrillation. We discuss methodologies of atrial effective refractory period assessment, identify which changes in refractoriness-related parameters reflect different degrees of electrical remodeling, and explore whether these parameters can be used to predict clinical outcomes.
Key Words: atrial fibrillation ■ biomarker ■ electrophysiology ■ refractory period
P
atients diagnosed with the same subtype of atrialfibrillation (AF) according to our current classifica-tion system may differ in symptom severity, se-verity of the arrhythmogenic substrate, and response
to antiarrhythmic therapy.1 Paradoxally, patients with
different AF subtypes may have similar severities of
the arrhythmogenic substrates. Hence, there is a need for an electrical biomarker as an indicator of the ar-rhythmogenic substrate underlying AF. The availability of such an electrical biomarker enables staging of AF and will improve patient-tailored therapy.
A well-known electrophysiological parameter that is affected by AF-induced electrical remodeling is the atrial effective refractory period (AERP). AERP shortens in response to accelerated activation fre-quencies, so-called rate adaptation of refractoriness. After deceleration, AERP prolongs again but even after sufficient time for recovery, AERP in patients with a history of AF remains relatively shorter. This indicates that AF inflicts permanent damage on car-diomyocytes’ rate adaptation capacities. In addition,
electrical remodeling can manifest heterogeneously throughout the atria, and subsequent dispersion of refractoriness is widely acknowledged as a key player in the pathophysiology of both onset and maintenance of AF.
If refractoriness is affected gradually as the arrhyth-mogenic substrate progresses, it could potentially be used as a biomarker for AF.
The aim of this review is to investigate whether atrial refractoriness can be used as an electrical biomarker of the arrhythmogenic substrate underlying AF. We discuss methodologies of AERP assessment, identify which changes in refractoriness-related parameters reflect different degrees of electrical remodeling, and explore whether these parameters can be used to pre-dict clinical outcomes.
RATE DEPENDENCY OF AERP
As mentioned above, AERP is rate dependent and adapts to the preceding cycle length. Duration of AERP
Correspondence to: Natasja M. S. de Groot, MD, PhD, Unit Translational Electrophysiology, Department of Cardiology, Erasmus Medical Center, Dr. Molewaterplein 40, 3015GD Rotterdam, the Netherlands. E-mail: n.m.s.degroot@erasmusmc.nl
For Sources of Funding and Disclosures, see page 10.
© 2020 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
JAHA is available at: www.ahajournals.org/journal/jaha
is directly related to the action potential duration (APD).2
Acute increase in activation rate during rapid stimulation
or tachyarrhythmia causes intracellular Ca2+ overload in
the cardiomyocytes.3 This triggers downregulation of
L-type Ca2+ channels and upregulation of slow rectifier K+
currents, resulting in faster repolarization and thus AERP
and APD shortening, so-called rate adaptation.4,5
Rate adaptation was first demonstrated in 20 patients without structural heart disease in whom episodes of pacing-induced AF shortened AERP at basic cycle lengths (BCLs) of 500 and 300 ms from 216±17 to 191±30 ms (P<0.0001) and 206±23 to
175±30 ms (P<0.0001), respectively.6 After a mean
period of 8.4±0.3 minutes, AERPs were restored to pre-AF values. Rate adaptation occurs immediately
after cycle length shortening2 and is progressive
when the tachycardia persists. In the goat model of AF, the AERP shortened from 131±11 to 106±17 ms after 24 hours of induced AF but shortened even
fur-ther to 70±12 ms after 43±34 days of pacing.7 The
shortest possible AERP is unknown, yet in both ex-perimental and clinical studies, a minimal AERP of 50
to 60 ms is commonly applied.8,9 However, the
ratio-nale for this cutoff value remains unclear, as there are no reports on assessment of the minimum duration of refractoriness.
Beat-to-beat changes in APD during steady-state pacing (APD alternans), related to cyclic fluctuations
in intracellular Ca2+ concentrations, were related to
onset of AF in humans.10–12 Varying APD morphology
was most prominent in the early repolarization phase, and recently involvement of changes in total outward
K+ currents was demonstrated as well in human left
atria (LA). During simulation of an action potential, using a mathematical model of human atrial
cardio-myocytes, replacement of K+ channels type Kv4.3 by
slower recovering type Kv1.4 (more fetal or undiffer-entiated variant), as occurs because of mechanical or endocrinological stress, increased occurrence of
APD alternans.13 APD alternans occurs only at rapid
pacing frequencies; in 12 patients with persistent atrial fibrillation (peAF), 13 patients with paroxysmal atrial
fibrillation (PAF), and 8 controls, APD alternans started at cycle lengths of 316±99, 266±19, and 177±16 ms,
respectively (P=0.02).11
“GOLD STANDARD”
REFRACTORINESS MEASUREMENTS
In general, refractoriness is determined by extrastim-uli (S2) pacing during electrophysiological studies and defined as the longest S1–S2 interval that fails to propagate a response. Pacing stimuli openvolt-age-gated Na+ channels, enabling Na+ influx,
result-ing in depolarization.14 The relation between stimulus
strength and AERP was examined in 25 patients with a history of syncope and atrial or ventricular tach-yarrhythmias; shortening of AERP attributable to in-creasing stimulus strength occurred progressively up to stimuli of relatively 5.3±1.7 mA at a BCL of 600 ms and 5.9±1.5 mA at a BCL of 300 ms (P=NS). At this point, refractoriness had been reached and AERP did not shorten further as stimulus strength was
increased up to 10 mA.15 Thus, there is an inverse
relationship between AERP and stimulation current. Therefore, AERP can be reliably compared between patients only when similar stimulus strengths are ap-plied during pacing.
Reliability of the premature stimulus methodology for AERP determination in nonuniform anisotropic car-diac tissue is questionable, as previously discussed by
Spach et al.16 The AERP is commonly defined as the
interval between pacing stimuli rather than the interval between atrial activations measured at the recording site. Therefore, frequency-dependent conduction de-lays during premature stimulation arising between the pacing and recording site result in apparently shorter AERPs. Distance between the pacing and recording electrode should therefore also be taken into account when comparing AERP between different atrial sites, but this is rarely reported.
Another parameter that has been used to esti-mate AERP is time to reach 90% of the action poten-tial repolarization (APD90). The reliability of APD90 measurements remains debatable, as when both AERP and ADP90 are determined in the same
in-dividual, substantial differences were observed.10
Comparing APD90 to AERP at a BCL of 600 ms, for example, 226±16 ms versus 211±24 ms in pa-tients with persistent AF (peAF, N=18), 250±35 ms versus 233±29 ms in patients with PAF (N=14), and 258±25 ms versus 229±19 ms in control subjects (N=9), respectively, were measured. Hence, these observations indicate that the APD90 is not a suit-able substitute for AERP. Validity of monophasic ac-tion potential catheters are debated as well, as they
are prone to movement artefacts.17
Nonstandard Abbreviations and Acronyms
AERP atrial effective refractory periodAPD action potential duration
APD90 action potential duration at 90% of
repolarization
BCL basic cycle length
PAF paroxysmal atrial fibrillation
peAF persistent atrial fibrillation
PV pulmonary veins
PVI pulmonary vein isolation
For both methodologies of measuring refractori-ness, using progressively faster steady-state pacing may result in different AERPs or APDs than the
extra-stimulus methodology,18 as refractoriness has more
time to adjust. Moreover, reports on the occurrence of APD alternans indicate that in some patients, repo-larization may be temporally irregular even during
con-stant stimulation rate.19
INDIRECT DETERMINATION OF AERP
As prior experimental and clinical studies demon-strated that the minimum or fifth percentile of the inter-val histogram corresponded to the AERP determined during extrastimuli protocols, these values have been widely accepted as a surrogate measure for AERP. In an isolated perfused canine model (N=8), high-den-sity (256 sites) epicardial AF recordings with a dura-tion of 10 seconds proved sufficient to estimate AERPby using the minimum AF cycle length.20 Likewise, in
patients with PAF (N=25), the fifth percentile approxi-mated AERP when calculated from at least 100 con-secutive fibrillation intervals measured endovascular at the high right atrium (RA), low RA, coronary sinus, or
oval fossa.21
Excitation of cardiomyocytes directly after the AERP is mandatory to derive the AERP from an interval his-togram. However, as reflected by the large variation in fibrillation intervals, cardiomyocytes are probably rarely excited at the exact moment that refractoriness ends, and as a consequence, an excitable gap is often
pres-ent.22 Also, when the fibrillation rate is low or regular,
lon-ger recordings may be required to estimate the AERP. Other ways to determine AERP during AF include slow fixed-rate pacing and entrainment. Duytschaever
et al8 used an experimental goat model to compare
various methodologies including an extrastimuli
pro-tocol (AERP, 70±12 ms); entrainment (77±17 ms; R2
correlation coefficient=0.88; P<0.01), fixed-rate pacing
(71±17 ms; R2=0.84; P<0.01) and the fifth percentile
AF cycle length (77±12 ms, R2=90, P<0.01) and found
that all approaches correlated well with the extrastimuli “gold standard.”
Even though these results look promising, it is im-portant to realize that the shortest interval measured probably represents the shortest possible AERP of local cardiomyocytes. The refractory period changes over time, as fibrillation intervals vary from beat to beat.
REFRACTORINESS IN
NONREMODELED ATRIA
Table 1 provides an overview of experimental and clini-cal studies assessing refractoriness in nonremodeled
hearts.2,6,7,10,21,23–28 In clinical studies, at BCLs of
400, 500, and 600 ms, AERP ranges from 213±35 to 266±37 ms, 215±29 to 277±42 ms, and from 227±20 to 291±53 ms, respectively. This table also shows that despite the fact that humans and animals share com-parable cardiac dimensions, absolute AERPs may still differ.
For example, at a BCL of 400 ms, AERP was 150±8 ms in canine RA and 146±19 ms in the LA and
RA of goats,7 compared with AERPs ranging from
213±35 to 266±37 ms (BCL, 400 ms) in human non-remodeled atria. Extrapolation of refractoriness mea-sures in animal models to humans should thus be done with caution.
Official reference values for “normal” refractoriness
are scarce. As previously discussed, only Daoud et al6
assessed refractoriness in nonremodeled human atria. AERP was determined in the RA of 20 patients without a history of AF (stimulus: 3× diastolic threshold; mean threshold, 0.7±0.2 mA). At BCLs of 500 and 350 ms, AERPs were 216±17 and 206±23 ms, respectively.
Various factors may influence AERP assessed during electrophysiology studies such as magnitude of decrements in extrastimuli and cardio-active medication
like antiarrhythmic drugs or anesthetics.23 In addition,
refractoriness is dependent on the measuring site, and
AERPs may vary from region to region.29,30 Finally,
hys-teresis of refractoriness measurements may also cause discrepancy in study results, as it has been reported that incremental extrastimuli lead to longer AERPs or APDs
than decremental extrastimuli in a canine model.31,32
However, as studies using both approaches to deter-mine AERP in human atria are not available from the literature, head-to-head comparison of incremental and decremental extrastimuli protocols is not possible.
SPATIAL DISTRIBUTION OF AERP IN
NONREMODELED ATRIA
In adult canines, APD in the RA shortened as
dis-tance to the sinus node increased.33 In another study,
AERPs measured using basket catheters in the lower part of the canine RA were indeed longer compared with the high part of the RA (BCL 400 ms, 111±23 ms versus 94±24 ms; P<0.01; BCL 300 ms, 104±20 ms versus 96±23 ms; P<0.01). AERP was also longer at the smooth posteroseptal RA than at the trabeculated RA free wall (102±25 ms versus 97±17 ms; P<0.05) at a BCL of 300 ms, suggesting that AERP may be
de-pendent of atrial wall morphology as well.34 However,
at a BCL of 400 ms AERP did not differ between the smooth and trabeculated wall.
Satoh and Zipes35 found longer AERPs in the
thin-ner medial RA free wall compared with the thicker lateral (terminal crest) region (BCL,300 ms; AERP, 149±12 ms
versus 133±8 ms; P<0.01) in 9 anesthetized open-chest dogs, suggesting that atrial refractoriness is related to wall thickness. Local variation in refractoriness were, however, not found in the RA of newborn dogs, indicating
that regional AERP differences develop during aging.16
AERP distribution was described in more detailed by
Vollmann et al.36 In 6 goats, AERPs were assessed at
11 epicardial regions, including the RA and LA free wall (array, 1×1.5 cm, 12 electrodes) and Bachmann’s bun-dle area (array, 10×1.3 cm, 56 electrodes). AERP was longest at mid-Bachmann’s bundle (AERP, 185±6 ms) and shortest at the LA free wall (AERP, 141±5 ms;
P<0.001). Other experimental studies also found that
AERPs in the LA are shorter.8,29,37–39
Table 1. Summary of Studies Investigating AERP in Nonremodeled Atria
Year of Publication, First
Author Subjects, N
Incremental or
Decremental Stimulus Strength Location BCL (ms) AERP (ms) Comment Experimental studies
1995, Wijffels7 Goats, 12 Incremental, 2-ms steps 4× threshold RA, LA Max 117±12 Small study
population 200 131±11
250 145±13
1995, Morillo24 Dogs, 10 Decremental, 10-ms steps 2×DT RA 300 147±11 Small study
population 400 150±8
1995, Wijffels7 Goats, 12 Incremental, 2-ms steps 4× threshold RA, LA 400 146±19 Small study
population Clinical studies
2001, Brundel23 13 … … LAA, RAA 250 184±5 Small study
population, anesthesia 300 224±16
1996, Daoud6 20 Incremental, 5-ms steps 3× threshold, mean
0.7±0.2 mA
RA (2 sites)
350 206±23 1995, Capucci21 10 Decremental, 1-ms steps 2.5×DT RA, CS,
or LA
400 266±37 Small study population 2001, Brundel23 13 … … LAA, RAA 400 252±34 Anesthesia
1987, Soni2 11 Decremental, steps: - 3 mA RA 436±81 225±29 BCL not
standardized 1995, Capucci21 10 Decremental, 1-ms steps 2.5×DT RA, CS,
or LA
500 267±42 Small study population 1996, Daoud6 20 Incremental, 5-ms steps 3× threshold, mean
0.7±0.2 mA
RA (2 sites)
500 216±17
2001, Brundel23 13 … … LAA, RAA 500 277±42 Anesthetics,
sternotomy 2010,
Centurion25
62 Decremental, 10-ms steps 2×DT RA, CS 500 215±29 1995, Capucci21 10 Decremental, 1-ms steps 2.5×DT RA, CS or
LA
600 281±35 Small study population 1998, Chen27 20 Incremental, 10-ms steps 2×DT RA 600 211±26
2001, Brundel23 13 … … LAA, RAA 600 291±53 Anesthetics
2002, Kim10 9 … … RA (6
sites)
600 227±20 Small study population 2016, Lee28 1308 Decremental, 10-ms steps 2× threshold RA 600 (in
93%)
233±31 BCL not standardized 1985, Alboni26 20 Decremental, 10-ms steps 2×DT RA 680±68 211±27 BCL not
standardized 1987, Soni2 11 Decremental, steps: - 3 mA RA 709±80 250±38 BCL not
standardized “-” indicates no details provided; AERP, atrial effective refractory period; BCL, basic drive cycle length; CS, coronary sinus; DT, diastolic threshold; LA, left atrium; LAA, left atrial appendage; RA, right atrium; and RAA, right atrial appendage.
Measurements of AERP at a BCL of 120 ms com-bined with tissue analysis in 9 mice atria demon-strated that LA AERP was shorter than the RA AERP (16.9±0.9 ms versus 19.8±1 ms; P<0.05) and that both total outward and inward rectifier K current density were increased in the LA suggestive of enhanced
ca-pacity for rate adaptation.39
Clinical studies have reported regional differences in AERP, but it is usually not measured at a high-reso-lution scale, or sites at which AERP is the shortest or longest are not described.
Remarkably, in few clinical studies, regional differ-ences in AERPs were compared between the nonre-modeled LA and RA. In 22 patients without AF, AERP was longer in the distal coronary sinus (BCL, 500 ms;
AERP, 244±30 ms) than in the RA (219±20 ms; P<0.01).40
This difference in AERP between the RA and coronary
sinus was also confirmed by other clinical studies.30,37
These observations contrast with many experimen-tal studies assessing regional differences in AERP, as mentioned above. However, patients in whom AF was repetitively induced were excluded, which may have caused a selection bias. There is also no evidence that AERPs in the LA and distal coronary sinus are comparable.
Whether electrical remodeling results in regional differences in AERP remains unclear. In goats, 4 weeks of atrial pacing (BCL, 150 ms) shortened AERPs, but it did not result in enhancement of re-gional AERP differences that were already present
during sinus rhythm.36
In 29 patients with a history of PAF, AERP at the pulmonary veins (PVs) was shorter than both the LA and the RA (PV, 174±62 ms; LA, 254±30 ms; RA,
221±29 ms; P=0.0001).41 In a similar patient
popu-lation, AERP was shorter at the distal PV than the PV-LA junction (PAF, N=48; AERP, 177±43 ms versus
222±30 ms, respectively; P<0.0001).42 Unfortunately,
spatial distribution of AERP between PV and LA has so far not been described in nonremodeled atria, so whether electrical remodeling affected regional differ-ences in AERP is unknown.
IMPACT OF AF ON REFRACTORINESS
In Table 2, clinical studies reporting on AERP meas-ured in patients with different subtypes of AF andcontrol patients are summarized.21,23,25,43-48 In general,
patients with a history of AF have shorter AERPs than
patients without AF.21,23,25,30,47–49 In patients with PAF,
at a BCL of 600 ms, AERP varied between 193±23 and 310±51 ms. This variation may be, as discussed above, attributable to many variables affecting AERP measurements, but it may also reflect heterogeneity in the AF substrates.
Interestingly, several investigators have reported shorter AERP in patients with PAF compared with
patients with peAF,10 which is in contrast with the
assumption that persistence of AF progressively shortens refractoriness. A possible explanation for this observation may be the increased prevalence of LA dilatation in patients with peAF, which prolongs
AERP.27,30,47,49
In absence of atrial dilatation, AERP is shorter in
patients with peAF than in patients with PAF.47 When
AERPs were longer in patients with peAF, this could be explained by atrial dilatation. Although tachycardia
initially causes upscaling of K+ ion channel
expres-sion and shortening of repolarization, atrial dilatation
leads to permanent reduction in both Ca2+ and K+
channel expression, resulting in prolonged AERP.4,50,51
Therefore, because of extensive electrical or structural remodelling in peAF, “normalisation” of AERP occurred and diminished differences between patients with PAF
and patients with peAF.10,30,49
FAILURE OF RATE ADAPTATION
Rate adaptation is a dynamic process reflected by rate adaptation curves, demonstrating the AERPs at different BCLs. Persistent shortening of AERP despite cycle length prolongation is referred to as failure of rate adaptation and causes attenuation of the rate adapta-tion curve. This phenomenon has been described in
isolated human atrial cells of dilated RA appendages,52
RA canine cells after fast rate activation,4,53 and several
clinical studies.23,54–56
In a detailed protocol, steepness of rate adapta-tion curves derived from the LA and RA appendage (BCL range, 250–600 ms) were compared between anesthetized patients with peAF (N=13), PAF (N=16), and no history of AF (N=13) before coronary artery
by-pass surgery.23 The slope of the rate adaptation curve
was less steep in patients with peAF compared with patients with PAF and controls (peAF, 87±57; PAF, 109±38; no AF, 138±33; P<0.05). This reduction in rate adaptation capacity correlated with a progressive
de-crease in protein expression of L-type Ca2+ channel,
Kv4.3, Kv1.5, hERG, minK, and Kir3.1 in both LA and RA appendages. These results indicate that decreas-ing steepness of the curve may relate to progressive ion channel dysfunction and thus to progression of the AF substrate.
Likewise, APD restitution, illustrated by fitted curves of APD90 plotted against preceding diastolic intervals, was less steep in 13 patients with peAF than in 27
pa-tients with PAF in the LA and PV area.19 Patients in
the PAF group showed a maximum APD restitution slope of 1.5±0.4, whereas in peAF group steepness was 0.7±0.2 (P<0.001). In the RA, however, slope was
1.3±0.4 in patients with PAF and 1.5±0.3 in patients with
peAF (P=NS). In contrast, Kim et al10 also measured
APD90 using a monophasic action potential catheter
at 6 locations in the RA and compared APD restitu-tion between patients with peAF, patients with PAF, and patients without AF. The mean slope was steeper Table 2. Summary of AERP Comparisons Between Different AF Subtypes
Year of Publication,
First Author Subjects, N Protocol
Recording Location BCL (ms) AERP (ms), Controls AERP (ms), PAF AERP (ms), peAF 1991, Kumagai48 12 peAF 12 controls Decremental, 10-ms steps HRA, CS … 238±23 215±1* 1995, Capucci21 25 PAF, 10 controls Decremental, 1-ms steps HRA, CS 600 231±36 193±2* 500 231±32 190±2* 400 234±34 178±4* 1998, Pandozi44 14 peAF Decremental, 2-ms
steps RA (mean of 5 sites) 700 207±19 600 203±18 500 198±17 400 191±15 300 180±15 1999, Kamalvand43 13 peAF, 8 controls Decremental, 10-ms steps, RAA 600 265 210* MLRA 600 228 215 RAA 400 270 200* MLRA 400 218 216 2000, Osaka46 10 peAF, 10 controls Decremental, 5-ms steps, 2× RA 600 247±25 224±13 RA 400 233±25 215±1* 2001, Brundel23 13 controls, 13 PAF, 16 peAF … RAA, LAA 600 291±53 222±1* 208±3* 500 277±42 224±2* 207±2* 400 252±34 216±2* 203±2* 300 224±16 202±20* 189±24* 250 184±5 185±19 172±17 2010, Centurion25 58 PAF, 62 controls Decremental, 10-ms steps RAA 500 215±29 208±2* 2013, Uhm47 343 PAF, 140 peAF Decremental, 1-ms steps HRA 500 233±29 231±27 LRA 500 229±31 228±27 PCS 500 251±3† 236±3† DCS 500 258±4† 237±3† Mean of all locations 500 243±27† 233±2†
2016, Nguyen45 28 PAF Incremental, 2-ms
steps HRA 600 310±51 PCS 600 289±36 DCS 600 289±50 Left PV 600 257±62 Right PV 600 265±62 Mean of all locations 600 283±30
AERP indicates atrial effective refractory period; BCL, basic drive cycle length; DCS, distal coronary sinus; HRA, high right atrium; LA, left atrium; LRA, low right atrium; MLRA, midlateral right atrial wall; PAF, paroxysmal atrial fibrillation; PCS, proximal coronary sinus; peAF, persistent atrial fibrillation; PV, pulmonary vein; RA, right atrium; and RAS, right atrial septum.
*Significantly different from controls.
†Significantly different between types of AF.
in patients with PAF (1.1±0.4) and peAF (1.4±0.3) than in control patients (0.5±0.3, P<0.01), but mutual differ-ences between AF subtypes were not significant.
The explanation for the contradicting results is un-known. However, there were differences in measuring sites, pacing protocols (eg, extrastimuli or dynamic
steady-state pacing10), and analysis methodologies,
each of which affect APD and APD restitution slope steepness. In addition, in both rate adaptation curves and APD restitution curves, a plateau phase was reached. Therefore, the range of BCLs or diastolic in-tervals along which mean curve steepness is calcu-lated may determine mean adaptation slope as well.
However, in all of the above-mentioned studies, it was not reported whether AF was induced or pres-ent before surgery. This may be of importance, as failure of rate adaptation restores after restoration of
sinus rhythm. Yu et al55 compared 19 patients with
peAF (>6 months) to 20 age-matched controls with-out a history of AF or atrial flutter. In the peAF group, rate adaptation curves constructed from AERPs at the RA appendage and distal coronary sinus 30 min-utes after cardioversion were less steep (RA: slope, 0.049±0.024 versus 0.074±0.016; distal coronary sinus: slope, 0.098±0.042 versus 0.162±0.040, re-spectively; both P<0.01). After 4 days of sinus rhythm, however, rate-adaptation curves no longer differed from the curves obtained from the control group (0.066±0.101 versus 0.162±0.040; P>0.05), indicat-ing that tachycardia-induced impairment of rate ad-aptation can be transient in nature. Additional studies are necessary to establish whether the slope of rate adaptation can be used to distinguish between dif-ferent AF subtypes, taking into account duration of sinus rhythm and AF episodes.
INTERREGIONAL VERSUS
INTRAREGIONAL DISPERSION OF
REFRACTORINESS
Heterogeneous manifestation of electrical remod-eling throughout the atria causes increased disper-sion of refractoriness, which is generally accepted as one of the key players in AF onset and maintenance. As a consequence, for example, unidirectional con-duction block of short-coupled ectopic beats caused by localized areas of prolonged refractoriness may initiate reentry.
There are generally 2 ways to measure “disper-sion of refractoriness.” In many studies, disper“disper-sion of AERP is defined as the maximum difference in AERP between varying atrial regions—in other words, inter-regional differences. For the sake of clarity, studies in which dispersion is defined as the difference between minimum and maximum AERPs from varying regions
are referred to as studying interregional dispersion. When mapping data with a high spatial resolution (in-cluding multiple AERPs per anatomic region) is used and intraregional differences are defined by a mathe-matical measure of variation, this will be referred to as
intraregional dispersion.
INTERREGIONAL DISPERSION
RELATED TO AF SUBTYPES
Several studies have compared interregional disper-sion of AERP between patients with and without AF. In each of these studies, a different set of recording sites was used, composed of only RA or both RA and LA recording sites, hampering comparison of study outcomes.
Interregional AERP dispersion between the high, mid, and lower RA wall was increased in 23 patients with PAF compared with 20 patients without AF
(45±28 versus 34±13; P<0.05).57 However, increased
interregional AERP dispersion between the RA ap-pendage and mid RA was demonstrated in 8 patients without AF compared with 13 patients with peAF
(dis-persion, 54 ms versus 18 ms, respectively; P<0.01).58
There were also no differences in interregional AERP dispersion when 6 measuring sites throughout the RA were compared between patients with peAF (N=18), PAF (N=14), and no history of AF (N=9). The average amounts of interregional dispersion in AERP were 32.4±30.3 ms (peAF), 41.7±27.4 ms (PAF), and 32.7±19.2 ms (no AF), respectively (P values not
provided).10
Likewise, when 3 RA and LA sites were combined, there was no difference in interregional dispersion be-tween patients with peAF (N=11), PAF (N=8), and no
history of AF (N=10).30 Other studies demonstrated in a
similar patient population that interregional dispersion of AERP was increased in patients with AF compared with patients without AF (peAF, N=18; PAF, N=22; no AF, N=19, corresponding to dispersions of 44.0±18.5, 49.3±29.9 and 23.5±14.1 ms, respectively; ANOVA,
P<0.01).49
In a larger cohort of patients with AF (PAF, N=343; peAF, N=140), interregional dispersion in AERP be-tween 4 LA and RA sites was 56.3±34.8 ms in PAF
versus 44.6±25.0 in peAF (P<0.001).47 Patients were
excluded when AERP could not be determined be-cause of AF induction. These excluded patients may be especially interesting as the arrhythmogenic sub-strate may be more pronounced, but it was not re-ported whether they were included in the peAF or PAF group.
In conclusion, evidence is conflicting with respect to interregional dispersion in AERP. Although interre-gional dispersion appears increased in patients with PAF
compared with patients without a history of AF, there is no evidence that interregional AERP dispersion is enhanced in patients with peAF compared with patients with PAF.
AERP in peAF was less dispersed than in patients
with PAF and even than in patients without AF.10,43,47 This
observation is not in line with the assumption that in-creased dispersion of AERP is associated with a more elaborate arrhythmogenic substrate in patients with peAF. It is unclear why reduced interregional dispersion was found in these patients with more progressive stages of remodeling. General shortening of the AERP may
re-duce regional differences. This was previously reported
by Wijffels et al7 who used an epicardial array containing
6 electrodes (interelectrode distance, 6–10 mm) to de-termine interregional dispersion of AERP between the RA appendage and LA appendage in 5 goats before AF induction, 24 and 48 hours after induction of sustained AF. Regional differences in AERP were 14, 22, 20, and 16 ms at BCLs of 400, 300, 250, and 200 ms, respec-tively, compared with 8, 8, 6, and 8 ms after 48 hours of AF (P value not provided). Although they described AF up to only 48 hours after induction, the same principle may apply to a general shortening of AERP in patients with peAF compared with patients with PAF.
Whether differences in interregional dispersion were mainly caused by shorter minimum or longer maximum AERPs was not reported in any of the clin-ical studies reporting on interregional dispersion of AERP. Also, as dispersion in refractoriness is already
demonstrated in closely adjacent RA sites,10 the
rel-evance of randomly chosen, widely spaced atrial sites for the assessment of interregional dispersion is questionable. Increased spatial density of AERP measurements leading to a more detailed assess-ment of AERP distribution throughout the atria (in-traregional dispersion) may be required to elucidate these remaining questions.
INTRAREGIONAL DISPERSION
RELATED TO AF SUBTYPES
Pacing in ex vivo rabbit atrial myocardium revealed that a minimum difference of 11 to 16 ms in AERP between ad-jacent electrodes (interelectrode distance unknown) was associated with local conduction block during
prema-ture extrastimuli.59 Dispersion of refractoriness will thus
lead to a frequency-dependent, scattered, and variable pattern of lines of conduction block, creating a substrate for the onset and maintenance of reentry circuits.
The relation between activation rate and dispersion in AERPs was first demonstrated in an experimental
canine model by Fareh et al.29 Dispersion of
refrac-toriness was defined as the coefficient of variation of AERPs (standard deviation/mean AERP) at 73 sites on the epicardium (interelectrode distance not provided).
The coefficient increased from 13.5% to 21.7% (P value not provided) during 24 hours of fixed-rate pacing (BCL, 150 ms) and was associated with increased sus-ceptibility to AF induction (r=0.81; P<0.001). In addition,
Li et al58 discovered a 3-fold increase in intraregional
dispersion of refractoriness in patients with PAF (N=21) compared with patients with acutely induced AF (N=12), defining dispersion as variance (squared SD) among the fifth percentile AF cycle length of 5 to 16 sites in RA and LA (AERP variance, 717±469 ms; acutely induced AF, 299±123 ms, respectively; P<0.05). The observed differences could mainly be attributed to shorter fifth percentile in the PAF group.
These studies support the hypothesis that in-creased intraregional dispersion of refractoriness causes increased susceptibility to AF. Unfortunately, no other studies have yet reported on the dispersion of refractoriness in patients with peAF. Whether intra-regional dispersion is best represented by these meth-odologies and whether they can be used to distinguish between different degrees of the arrhythmogenic sub-strate is yet to be discovered.
PREDICTION OF AF ONSET
In 734 patients with atrioventricular nodal reentrant tachycardia or a concealed bypass tract (N=1308; age, 44±16 years), spontaneous onset of AF within 12 years was enhanced if AERP at the high RA was >280 ms (BCL, 600 ms in 93%; hazard ratio adjusted
for age, 2.08; P =0.041).28 This seems to contrast
with the association between short AERPs and AF. However, patients with AERP ≥280 ms (n=34; 10.3%) also had larger LA size (41±6 mm versus 36±6 mm;
P<0.001), which, as previously discussed, prolongs
AERP. When an AERP of 280 ms is compared with AERPs measured in nonremodeled RA of nonanes-thetized patients (Table 1), 280 ms indeed seem dis-proportionally long.
Interregional dispersion in AERP of >76 ms between high RA, low RA, and distal and proximal coronary sinus was related to AF onset within 24 months after abla-tion of an atrioventricular bypass or slow atrioventricu-lar node pathway in 845 patients (area under the curve,
0.896; 95% CI, 0.833–0.959; P<0.05).60 Sensitivity and
specificity were not provided, nor was the stimulation protocol. Although prior atrial tachycardia was an exclu-sion criterion, the authors mention AF recurrence rather than onset, suggesting that AF had occurred before.
PREDICTION OF SUSCEPTIBILITY TO
AF INDUCTION
AERP has also been used to predict susceptibil-ity to artificial AF induction. In most studies, it was
demonstrated that enhanced susceptibility to AF induction was associated with shorter AERPs. In both isolated and in vivo canine atria, shortening of AERP was associated with increased inducibility of
sustained AF.61,62 Pharmacologically induced AERP
shortening increased susceptibility to AF induction
in dogs,63 whereas AERP prolongation reduced AF
inducibility in swine.64
In clinical studies, there was no relation between AERP and AF inducibility in patients with or without structural heart disease and with supraventricular tachycardia, when defining successful induction as
AF lasting either >10 seconds (N=50)65 or >5 minutes
(N=44).66,67 A possible explanation for the disparate
outcomes is that AERP by itself does not reflect the ar-rhythmogenic substrate. In a canine model, increased intraregional dispersion of AERP, defined as covari-ance among 96 epicardial sites, was an independent risk factor for AF induction (stepwise multilinear
re-gression; P<0.0001), whereas ERP alone was not.29
Interregional dispersion was related to successful AF induction both in experimental and clinical stud-ies but could not be used to identify patients at risk of
AF persistence.62,67 In a canine model (anesthesized,
hypothermic, vagal stimulation), interregional disper-sion between the sinus node area, the low posterior RA, and the distal coronary sinus was increased in dogs susceptible to AF induction (59±24 ms versus
29±18 ms; P<0.001).62 Similarly, in patients with a
his-tory of PAF, interregional dispersion between the high RA, low RA, interatrial septum, and proximal and distal coronary sinus was larger in the AF inducible group (N=22; 105±78 ms) than in the noninducibility group
(N=11; 49±20 ms; P<0.05).68 In a follow-up study,
how-ever, interregional dispersion did not differ between pa-tients in whom induced AF terminated spontaneously
or persisted.67
The occurrence of APD alternans may also pre-dict susceptibility to AF induction. In a small study of 12 patients with peAF, 13 patients with PAF, and 8 patients without a history of AF, APD alternans
pre-ceded all successful AF inductions.11 In cases where
APD alternans had disappeared because of loss of capture, AF was noninducible. In addition, in 19 patients without structural heart disease, especially discordant APD alternans was related to AF
induc-ibility.69 Discordant alternans was evoked in 13 of 19
(46%) patients and followed by AF initiation in 8 of them (P=0.012).
It is unclear, however, whether susceptibility to AF induction relates to AF onset or recurrence in real life. Moreover, induction protocols vary considerably, jeop-ardizing validity and reproducibility of study results, as susceptibility to AF induction is strongly dependent on, for example, the number of induction attempts and
stimulus strengths.66
PREDICTION OF EARLY
POSTOPERATIVE AF
In 56 patients admitted for coronary artery bypass grafting (AF, N=18; no AF, N=38), interregional disper-sion of refractoriness (high RA, posterolateral RA, dis-tal coronary sinus) was an independent predictor of postoperative AF incidence (odds ratio, 1.29; 95% CI,
1.12–1.47; P<0.001).70 It was not reported which patient
group showed more interregional dispersion.
PREDICTION OF SUCCESSFUL
ABLATIVE THERAPY
In 67 patients with both an accessory pathway and AF, the relation between interregional dispersion and recurrence rate was used to predict which pa-tients benefit from PV isolation (PVI) concomitant to ablation of the accessory pathway. Concomitant PVI was performed in 29 patients. Interregional dispersion of >75 ms was related to AF recurrence within 36 months (sensitivity, 70%; specificity, 92%;
P=0.003). If dispersion was >75 ms (PVI, N=9; no
PVI, N=11), concomitant PVI resulted in lower recur-rence rates (2 [18.2%]) than pathway ablation alone (7 [77.8%]; P=0.012). When dispersion was <75 ms, no difference in recurrence rates was established
be-tween the PVI (N=18) and non-PVI groups (N=25).71
The way in which patients were assigned to the PVI or non-PVI group is not described; however, interre-gional dispersion was similar in both groups. These results suggest that regional differences in refractori-ness may aid in selecting patients who will benefit most from additional PVI ablation therapy, but addi-tional research will have to be performed to confirm and solidify these outcomes.
CURRENT APPLICABILITY
OF REFRACTORINESS AS AN
ELECTRICAL BIOMARKER
AF-induced electrical remodeling is related to AERP shortening, dispersion of refractoriness, and attenu-ated slopes of AERP–rate adaptation curves. However, none of the reviewed parameters seem to have a strict linear relation with the arrhythmogenic substrate underlying AF. Although differences in refractoriness have been demonstrated between patients with dif-ferent AF subtypes, considerable overlap in AERPs is observed. Construction of, for instance, receiver operating characteristic curves to further examine the predictive value of AF may be useful.
In many studies, environmental factors influencing AERP are not fully measured or documented. Those
factors may include the pacing protocol (measuring site, stimulus strength, BCL), data processing (eg, choosing the appropriate blanking period for determination of local activation time), atrial dilatation, stimulation of the autonomous nervous system, cardio-active medica-tion (usage of antiarrhythmic medicamedica-tion, anesthetics), and phases of electrical (reverse) remodeling (such as time since AF onset/induction, time since conversion to sinus rhythm). Therefore, standardized pacing proto-cols and elaborate documentation are required to ac-curately measure AERP and compare study outcomes. There are several hurdles to overcome in order to establish whether AERP is a suitable biomarker for staging of AF. For example, as there are most likely both interregional and intraregional differences in AERPs, a detailed map of refractoriness is essential to gain insight into dispersion in refractoriness in both nonremodeled and remodeled atria.
Determination of AERP during AF, however, as is required for patients in whom cardioversion cannot be accomplished, may be even more problematic. As discussed above, the reliability of the minimum or 5th percentile of the AF cycle length histogram as a re-flection of AERP is questionable. In addition, the AERP changes from beat to beat because of variability in pre-ceding fibrillation intervals.
Another patient group in whom AERP may not have been determined accurately so far includes patients who are susceptible to AF induction. They are often excluded from analysis when no AERP can be deter-mined because of repetitive AF induction. This could have resulted in distortion of study results, as refrac-toriness especially in these patients may be altered. Using incremental instead of decremental extrastimuli protocols may reduce this problem, as there will be no need for repetitive electrical cardioversion and restart-ing of the pacrestart-ing sequence.
At present, interregional dispersion has been stud-ied more frequently than intraregional dispersion of AERP, which does not seem to reflect the arrhythmo-genic substrate adequately and is therefore unsuitable as a biomarker. Research into the prognostic value of AERP-derived parameters is limited and needs further investigation.
In the future, pairing refractoriness with addi-tional electrical biomarkers may be considered as well, as AERP is not the only factor that influences susceptibility to AF. Whereas electrical remodeling appears to play a key role in the initiation of AF, addi-tional structural remodeling has proven to be crucial for persistence of the tachyarrhythmia. Progressive wavelength shortening was demonstrated in a canine
model after rapid pacing (BCL, 150 ms)24 and in goats
with artificially sustained AF,7 increasing susceptibility
to AF induction and enhancing spatiotemporal disor-ganization of waves in persistent AF. This occurred a
considerable period after AERP had reached a new steady state, increasing stability of AF. This indicated that electrical remodeling alone may not cover the full extent of the arrhythmogenic substrate.
AF persistence may depend on the combination of electrical (AERP shortening) and structural remodeling (such as reduced conduction velocity attributable to, eg, fibrosis or nonuniform anisotropy) rather than AERP
alone.72 Therefore, other dynamic electrical
character-istics such as conduction velocity may also be suitable as a biomarker.
ARTICLE INFORMATION
Affiliations
From the Department of Cardiology, Erasmus Medical Center, Rotterdam, the Netherlands.
Sources of Funding
Prof Dr de Groot, MD, PhD, is supported by grants from the Investigator-Initiated Study Program of Biosense Webster, Inc. (IIS-331 Phase 2), the CardioVascular Onderzoek Nederland (grant number 914728), and Nederlands Wetenschappelijk Onderzoek-Vidi (grant number 91717339) and Medical Delta.
Disclosures
None.
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